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Seasonal influenza epidemics are associated with a 2-fold increase in deaths and mortality, which is especially high in groups at risk (1). Acute myocarditis during influenza infection is a well-known complication, and the clinical expression varies from asymptomatic to fatal congestive cardiac failure (1). The diagnosis of myocarditis remains a challenge because of the nonspecific pattern of clinical presentation and the lack of a standardized diagnostic process. Cardiac magnetic resonance (CMR) is a widely used tool for diagnosing myocarditis (2). The aim of our study was to evaluate a population positive for H1N1 influenza and those with symptoms or signs suggesting cardiac involvement to be referred for further CMR evaluation.

We screened 200 previously healthy adults age 32 ± 5 years (range 19 to 45 years of age), with nasopharyngeal smears positive for H1N1 influenza by polymerase chain reaction assay, who presented with symptoms of influenza. Patients who had received influenza vaccinations in the past 12 months and those with active chronic illness, histories of drug abuse, pacemakers, defibrillators or metallic clips, and/or impaired renal function were excluded. Thirty-two patients with symptoms or signs suggesting cardiac involvement (chest pain, arrhythmia, shortness of breath, abnormal electrocardiographic [ECG] findings, or abnormal cardiac enzymes) were referred for further cardiac evaluation. ECG findings were abnormal in 16 of 32 patients. All 32 patients were referred for CMR, and their data were compared with those of 32 age-matched controls. All patients and controls gave written consent, and the study was approved by the hospital's ethics committee.

CMR evaluation was performed within 7 to 14 days after the onset of symptoms. Repeat CMR was performed 3 months after the initial presentation. CMR evidence for myocarditis was defined according to published criteria as determined from T2-weighted (T2-W) and T1-weighted (T1-W) images before and after contrast media injection and late gadolinium enhancement (LGE) images. Results were considered positive if at least 2 of 3 imaging sequences showed positive results (2). CMR studies were performed using a surface coil in a 1.5-T system. ECG-triggered short inversion time inversion recovery T2-W multislice spin-echo sequences and T1-W multislice spin echo images were also obtained in the axial orientation with identical parameters before and after an intravenous bolus of 0.1 mmol/kg gadolinium diethylenetriaminepentaacetic acid. Measurements after contrast injection were started within 1 min of injection (early T1) in the same area as for T2-W imaging. Immediately after the second set of T1-W images was obtained, 0.1 mmol/kg gadolinium diethylenetriamine pentaacetic acid was administered again, and LGE images were taken 15 min later. Images were analyzed according to previously described protocols. For the assessment of left ventricular (LV) function, a steady-state free precession sequence was used. Images were evaluated by 2 independent readers, and the kappa value was 0.85.

Continuous data were expressed as mean ± SD. Statistical analysis was performed using Mann-Whitney U tests. A p value <0.05 was considered to indicate statistical significance.

Thirty-two patients with symptoms or signs suggesting cardiac involvement were referred for further cardiac evaluation. On admission, 13 patients presented with mild chest discomfort and dyspnea, 14 with sinus tachycardia, and 5 with severe chest pain radiating to both arms. None of the patients presented with ventricular tachycardia, bundle branch or atrioventricular block, or evidence of LV and/or right ventricular dysfunction. Cardiac enzymes were evaluated in all 32 patients.

The results of CMR were positive for myocarditis in all patients with severe chest pain, ST-segment elevation, and/or increased cardiac enzymes, as well as in 3 of 14 patients with sinus tachycardia and 2 of 13 with mild chest discomfort and dyspnea (Table 1). In the 10 patients with CMR-documented myocarditis, the mean LV end-diastolic volume was 124.8 ± 14.7 ml, the mean LV end-systolic volume was 44.0 ± 1.63 ml, and the mean LV ejection fraction was 64.7 ± 1.6% (within normal limits). Wall motion abnormalities were not identified in any patient.

Clinical, ECG, Laboratory and CMR Findings in Patients Positive for Myocarditis on CMR

In the T2-weighted images, the signal ratio of myocardium to skeletal muscle was 1.9 ± 0.16 (control value 1.56 ± 0.12, p < 0.05), indicative of edema. Focal areas of high T2-signal were not identified. In the T1-W images, the early gadolinium enhancement ratio was 9.22 ± 6.05 (control value 3.08 ± 0.03, p < 0.05). LGE areas were identified in all patients positive for myocarditis. They were patchy, epimyocardial, or endomyocardial, and distributed mainly in the inferior and lateral walls, although in 2 patients, areas of LGE were also identified in the intraventricular septum. Their total extent was 6.1 ± 4.55%. All patients with abnormal cardiac findings were young, with concurrent pneumonia and no histories of systemic or coronary artery disease. No correlation between heart involvement and patients' demographic data was identified. Re-evaluation by CMR 3 months later revealed normal findings in all patients (Fig. 1). Clinical and CMR findings of patients positive for myocarditis are presented in Table 1.

Area of late gadolinium enhancement (LGE) in the inferior wall of a patient with myocarditis during H1N1 infection (left) and disappearance of LGE on follow-up cardiac magnetic resonance 3 months later (right).

The global burden of influenza is believed to be 3 million to 5 million cases of severe illness and up to 300,000 deaths annually. Although myocardial involvement typically is considered a rare complication of influenza, the true incidence of myocardial inflammation in influenza, especially in H1N1 influenza, is not well known, mainly because of limited accuracy of standard diagnostic tools.

CMR can easily visualize the entire myocardium, and it is ideal for a focal process such as myocarditis. The imaging protocol used in this study captures the 3 basic phenomena of the myocardial inflammatory response (edema, increased capillary leakage, and focal necrosis or fibrosis). A combined CMR approach using T2-W early gadolinium enhancement and LGE has sensitivity of 67%, specificity of 91%, and diagnostic accuracy of 78% in the detection of viral myocarditis (2).

The CMR studies in our patients identified the presence of myocarditis in all patients with severe chest pain, ST-segment elevation, and/or increased myocardial enzyme levels and also in some patients with only sinus tachycardia or chest discomfort and/or dyspnea. The LV ejection fraction was preserved, although the results of CMR examination were positive for the presence of myocarditis. These findings are in agreement with those of previous studies describing the variety of clinical presentations of myocarditis. Our data also showed that myocardial involvement in H1N1 influenza is frequent and can be assessed by CMR, which therefore could be used to rule in or rule out myocardial involvement in H1N1 influenza, even in the absence of other indicators of myocarditis, if myocardial involvement is clinically suspected.

The present study had some limitations: 1) patients presented without evidence of heart failure; 2) biopsies were not clinically indicated and thus not performed; 3) children or patients with severe and/or fulminant forms of H1N1 influenza were not included; and 4) only short-term follow-up was performed.

According to our findings, in a young, otherwise healthy population, myocardial inflammation in H1N1 influenza is frequent but appears to be mild. In patients with H1N1 influenza and clinically suspected myocardial involvement, CMR is a valuable tool to assess for myocarditis early in the course of H1N1 influenza and during follow-up, even in the absence of other clinical markers of myocarditis.